The major problem in the field of cardiac transplantation is the lack of human organs and tissues for those who need them. This problem is so severe that by some estimates only 5-15% of the heart transplants needed are carried out;this shortage may worsen as medical advances allow diseases of aging, such as diabetes and atherosclerosis, to be increasingly prevalent. One approach to overcoming this problem is to use animal organs in lieu of human organs for transplantation, that is xenotransplantation. However, cardiac xenotransplantation is not presently feasible because the immune system of the recipient immune reacts severely with the graft causing vascular diseases such as hyperacute and acute vascular rejection, and possibly chronic rejection. Triggered by the binding of xenoreactive antibodies and the activation of complement, acute vascular rejection destroys organ xenografts over a period of days to weeks and is now the main impediment to clinical application of xenotransplantation. Despite the severity of this condition, acute vascular rejection is not an invariable outcome of cardiac xenotransplantation. Under some conditions, such as when xenoreactive antibodies are temporarily depleted, a graft may seemingly acquire resistance to injury by anti-donor antibodies, a condition referred to as accommodation. This application proposes studies that will address the problem of acute vascular rejection and test new strategies for understanding and generating accommodation. The first objective will be to determine which antigens provoke rejection of organs from Gala1-3Gal-deficient pigs. Since rejection of these organs appears also to be caused by acute vascular rejection, novel strategies will be tested for abrogating the B cell responses causing this condition. A second objective will be to induce resistance of cells and organs to acute vascular rejection, thus determining how accommodation can be more reliably induced. New strategies toward this end will be tested. Fulfilling these objectives will yield much progress toward the preventing of acute vascular rejection or promoting the occurrence of accommodation of cardiac xenografts and allografts.